Glaucoma is an optic neuropathy resulting in irreversible loss of visual function over time. Glaucoma is considered the second leading cause of blindness in the world. Predictions are for approximately 80 million people afflicted with glaucoma worldwide by 2020 (Quigley and Broman, Br J Ophthalmol 2006). Frequently, but not always, glaucoma is associated with elevated IOP which is recognized as an important risk factor for the disease. Ocular hypertension, a condition associated with elevated IOP that has not yet progressed to causing irreversible glaucomatous damage, is believed to represent the earliest stage of glaucoma. Therapeutic agents devised for the treatment of glaucoma and ocular hypertension have been designed to lower IOP, which remains the sole, proven treatable risk factor of the disease.
The drugs currently used for the treatment of glaucoma and ocular hypertension include prostaglandin analogs (e.g., latanoprost, bimatoprost, travoprost, tafluprost), beta-adrenergic blockers (e.g., timolol, betaxolol, levobunolol), alpha-adrenergic agonists (e.g., brimonidine, paraamino-clonidine), parasympathomimetics (e.g. pilocarpine, carbachol, acethylcholineesterase inhibitors), sympathomimetics (e.g., epinephrine, dipivalyl-epinephrine), carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide). Pressure in the eye (IOP) is determined by the balance of aqueous humor production and aqueous humor outflow. It is generally accepted that elevated IOP is the result of compromised aqueous humor outflow. Thus, compounds that increase the outflow of aqueous humor are considered preferable for reducing IOP in glaucoma and ocular hypertensive patients. Prostaglandin analogs, sympathomimetics and parasympathomimetics are believed to decrease IOP by increasing aqueous outflow, whereas beta-blockers, alpha-adrenergic agonists and carbonic anhydrase inhibitors are believed to decrease IOP by reducing aqueous humor production. Prostaglandin analogs cause undesirable effects, such as increased conjunctival hyperaemia and iris hyperpigmentation, for example. Parasympathomimetics induce undesirable accommodative changes leading to blurring of vision. Sympathomimetics can also stimulate aqueous humor production which partially counteracts their effect on aqueous humor outflow and thus limits their resultant effect on IOP regulation. Some antiglaucoma drugs, e.g., timolol, produce systemic effects. These adverse events can lead to poor patient compliance and may necessitate withdrawal of drug therapy.
As a consequence, a need still exists to identify and develop anti-glaucoma drugs that specifically enhance aqueous humor drainage from the eye and, preferably, have a more limited adverse event profile.
Of the two primary aqueous humor outflow pathways in the eye, the conventional/trabecular outflow pathway represents the more attractive target since it is the site of outflow obstruction that leads to ocular hypertension. As reviewed by Ellis (Cell Physiol Biochem 2011) nitric oxide donors and guanylate cyclase activators have been shown to decrease IOP in humans, rabbits and monkeys. Nitric oxide is an endogenous activator of the soluble guanylate cyclase enzyme which in turn catalyzes the generation of cyclic GMP as a second messenger molecule. The role of the nitric oxide—soluble guanylate cyclase—cyclic GMP pathway in IOP regulation is well established (Ellis, Cell Physiol Biochem 2011). Components of this pathway, such as endothelial and neuronal type nitric oxide synthases responsible for the endogenous generation of nitric oxide, are present in the outflow pathway tissues. Thus, stimulation of sGC represents a novel ocular anti-hypertensive approach, regardless of whether the reduction in IOP through enhancement of aqueous humor drainage is caused by modulation of cell volume of trabecular meshwork or Schlemms Canal cells (Ellis, Cell Physiol Biochem 2011) or trabecular meshwork contractility (Stumpff and Wiederholt, Ophthalmologica 2000). Modulation of cell volume and/or contractility of structures in the trabecular outflow pathway had been proposed as mechanistic rationales for IOP regulation.
In U.S. Pat. No. 5,652,236, a method for reducing IOP in the mammalian eye by administration of guanylate cyclase inhibitors is claimed. In that context, it was surprising that guanylate cyclase activators were found to also reduce IOP.